The chemical entity 5-(3′,5′-dimethyl phenoxy)methyl-2-oxazolidinone of formula (I),
generically known as Metaxalone, is an interneuronal blocking agent. It is used in physical therapy and other measures to relax muscles and relieve pain and discomfort caused by strains, sprains and other muscle injuries.
The drug, which was approved in January, 1962 in the U.K and in August, 1962 in the USA, has since been marketed under the brand name Skelaxin® for the abovementioned indications.
Inspite of metaxalone being in therapeutic use for the last 43 years, however, it is surprising that it is still not listed by US and European Pharmacopoeias.
Essentially, two methods for the synthesis of Metaxalone have been reported, which are summarized in Schemes-1 and 2 given herein below:
    X=OH, NH2, Cl, Carbamate etc.    Y=NH2, O—CH3, O—CCl3, Cl    Z=NH2, O—CH3, O—CCl3, OEt
The method summarized in Scheme-1 and as disclosed in U.S. Pat. No. 3,062,827 and WO03061552 comprises the fusion of 3-(phenoxy)-2-hydroxy-propyl-1-substituted compounds (1) with 1, 1 disubstituted carbonyl compounds (2).

Similarly the method described in Scheme-2 and disclosed in U.S. Pat. Nos. 3,446,814 and 6,562,980 comprises a reaction between Triglycidyl isocyanurate (TGIC, 3) and a suitable Phenol (4).
With regard to the method summarized in Scheme-1, typically the reaction of 3-(phenoxy)-2-hydroxy-propyl-1-substituted compounds (1) with 1, 1 disubstituted carbonyl compound (2) is carried in the presence or absence of solvents at temperatures between 50-150° C. (U.S. Pat. No. 3,062,827) and 170-200° C. (WO03061552) for 3-5 hours. The product i.e. Metaxalone is isolated from solvents like ethyl acetate, benzene, toluene, xylene, cyclohexane, methanol, ethanol, butyl acetate, acetone, methylisobutylketone, ether, tetrahydrofuran, dioxan, dimethoxyethane etc.
Similarly, the method described in Scheme-2 involves a reaction between Triglycidyl isocyanurate (TGIC, 3) and a suitable Phenol (4) in the presence of base and solvents such as benzene, toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, acetone etc at reflux temperatures for 12 to 24 hours. The product obtained i.e. Metaxalone is recrystallised from solvents like chlorobenzene, water or ethyl acetate.
While any physical, chemical, or physicochemical properties of Metaxalone isolated from most of the methods mentioned hereinbefore is not disclosed, however, the only report or disclosure of any such properties find mention in the following cases:    i) Crystallization from dry ethyl acetate as disclosed in U.S. Pat. No. 3,062,827, which further mentions the melting point of the product to be 121.5-123° C.;    ii) Crystallization from chlorobenzene as disclosed in U.S. Pat. No. 3,446,814, where the product obtained has a melting point of 122° C.; and    iii) Crystallization from benzene, toluene, xylene, cyclohexane, methanol, ethanol, ethyl acetate, butyl acetate, acetone, methylisobutylketone, ether, tetrahydrofuran, dioxan, dimethoxyethane etc., as disclosed in WO03061552, which mentions that the product obtained has purity greater than 99%.
The abovementioned documents, apart from mere mention that the product i.e. Metaxalone could be recrystallised from various solvents mentioned therein do not provide any details of the crystallization conditions or parameters such as temperature, solvent proportion, rate of crystallization etc. This would be particularly evident from the disclosures contained in Example-1 of U.S. Pat. No. 3,062,827 and Example-7 of U.S. Pat. No. 3,446,814.
While Metaxalone has been in clinical practice since 1962 and, moreover, since it is known to be produced by the methods summarized in Schemes-1 and 2, however, because of its low aqueous solubility, the drug product (finished dosage form) or the drug substance [Bulk Active Pharmaceutical Ingredient (API)] made from different manufacturing batches or from different manufacturing locations have not been found to be uniform or consistent in their bioavailability.
Many studies and attempts have been made to address the issue of inconsistent bioavailability, of which two noteworthy disclosures are given hereinbelow:                a) Michael Scaife et al in U.S. Pat. No. 6,407,128 have reported a method to increase the bioavailability of Metaxalone by the administration of an oral dosage form with food, wherein the administration occurs between 30 minutes prior to or 2 hours after consuming food.        b) Dharamadhikari et al in WO2004019937 report that if the Metaxalone used is in a “pharmaceutically acceptable solubility-improved form”, the bioavailability is enhanced. “Pharmaceutically acceptable solubility improved form” referred to therein comprises of micronised, high-energy crystalline or amorphous form of Metaxalone or salt form of drug.        
Dharamadhikari et al further mention that the “Pharmaceutically acceptable solubility improved form” could be obtained by conventional methods such as milling, crystallization, sublimation, or spray drying etc. or through known methods of forming a solid dispersion of the drug in a carrier such as spray drying, melt dispersion, solvent evaporation etc.
Further, they also recommend addition of excipients like solubilizing agents, surfactants, pH control agents, and complexing agents to enhance the bioavailability.
In addition, Dharamadhikari et al mention the importance of particle size and specific surface area in obtaining the desired bioavailability.
From the teachings of WO2004019937, it would be abundantly evident that the method (s) disclosed therein primarily relate to obtaining a material of reduced particle size or increased surface area which is a technique widely practiced in pharmaceutical area and lacks any innovativeness.
While WO2004019937 mentions utilization of other forms of Metaxalone, such as high energy crystalline/amorphous or salt form, however, like the prior art documents, mentioned hereinearlier, it i.e. WO2004019937 fails to provide any enabling disclosure as to how such forms could be obtained as well as is silent about the bioavailability of the specified forms of Metaxalone.
As mentioned hereinbefore, since the only enabling disclosure contained in WO2004019937 refers to a micronised form it would endorse the present inventors view that WO2004019937 primarily relates to the studies on the bioavailability of a micronised form of Metaxalone.
Micronisation or otherwise referred to as milling requires special machines or equipment which calls for not only capital investment but also increases the cost of manufacture.
To summarize, the prior art methods for the manufacture of Metaxalone:                i) Do not provide any physical, chemical, or physicochemical properties of the product obtained apart from a mere mention of melting point and purity in few cases.        ii) Do not provide any details of the crystallization conditions or parameters such as temperature, solvent proportion, rate of crystallization etc; and        iii) Are known to produce products, which in general are found to be inconsistent in their bioavailability.        
Further, the only reports related to improvement of bioavailability of Metaxalone prescribe that the drug be either taken along with food or recommend that the bulk drug should be in a form which has a specific particle size or surface area.
The latter especially calls for micronisation techniques, which are not only tedious and lengthy but also result in loss of precious material, thereby increasing the cost of manufacture of Metaxalone.
As the drug i.e. Metaxalone is not listed in the US, EP or for that matter in the Pharmacopoeias of other countries, and, moreover, since there is no Pharmacopoeial Reference Standard available, it would be difficult for a Manufacturer to not only set a specification for his/her product but also to predict whether his/her product would be bioavailable.
Therefore There exists a longfelt need for either a manufacturing process for either the bulk or dosage form of Metaxalone, which would be simple, convenient and economical to produce and which, moreover, would impart consistent bioavailability of the drug substance or drug product.
The present invention is a step forward in this direction and provides crystalline forms of Metaxalone, hitherto unknown and which are bioavailable.